title: Metabolism and disposition of oral dabrafenib in cancer patients: proposed participation of aryl nitrogen in carbon-carbon bond cleavage via decarboxylation following enzymatic oxidation.
abstract: A phase I study was conducted to assess the metabolism and excretion of [(14)C]dabrafenib (GSK2118436; N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt), a BRAF inhibitor, in four patients with BRAF V600 mutation-positive tumors after a single oral dose of 95 mg (80 µCi). Assessments included the following: 1) plasma concentrations of dabrafenib and metabolites using validated ultra-high-performance liquid chromatography--tandem mass spectrometry methods, 2) plasma and blood radioactivity, 3) urinary and fecal radioactivity, and 4) metabolite profiling. Results showed the mean total recovery of radioactivity was 93.8%, with the majority recovered in feces (71.1% of administered dose). Urinary excretion accounted for 22.7% of the dose, with no detection of parent drug in urine. Dabrafenib is metabolized primarily via oxidation of the t-butyl group to form hydroxy-dabrafenib. Hydroxy-dabrafenib undergoes further oxidation to carboxy-dabrafenib, which subsequently converts to desmethyl-dabrafenib via a pH-dependent decarboxylation. The half-lives for carboxy- and desmethyl-dabrafenib were longer than for parent and hydroxy-dabrafenib (18-20 vs. 5-6 hours). Based on area under the plasma concentration-time curve, dabrafenib, hydroxy-, carboxy-, and desmethyl-dabrafenib accounted for 11%, 8%, 54%, and 3% of the plasma radioactivity, respectively. These results demonstrate that the major route of elimination of dabrafenib is via oxidative metabolism (48% of the dose) and biliary excretion. Based on our understanding of the decarboxylation of carboxy-dabrafenib, a low pH-driven, nonenzymatic mechanism involving participation of the aryl nitrogen is proposed to allow prediction of metabolic oxidation and decarboxylation of drugs containing an aryl nitrogen positioned α to an alkyl (ethyl or t-butyl) side chain.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.A.B., D.B.M.-F., K.E.J., D.M.K., P.D.G., L.E.R.-P.); Department of Clinical Pharmacology Modeling and Simulation (D.O., N.N.) and Department of Oncology R&D (S.W.C.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania (S.C.B., J.L.A.); and Comprehensive Clinical Development NW, Tacoma, Washington (R.A.M).
authors.forename: David A
authors.initials: DA
authors.lastname: Bershas
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
authors.forename: Donna B
authors.initials: DB
authors.lastname: Mamaril-Fishman
authors.forename: Noelia
authors.initials: N
authors.lastname: Nebot
authors.forename: Stanley W
authors.initials: SW
authors.lastname: Carson
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Blackman
authors.forename: Royce A
authors.initials: RA
authors.lastname: Morrison
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Adams
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Jurusik
authors.forename: Dana M
authors.initials: DM
authors.lastname: Knecht
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gorycki
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Richards-Peterson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002244:Carbon / Q000378:metabolism*; D003653:Decarboxylation / Q000502:physiology*; D005243:Feces / Q000737:chemistry; D005260:Female; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D009584:Nitrogen / Q000378:metabolism*; D010084:Oxidation-Reduction; D010091:Oximes / Q000378:metabolism*; D055815:Young Adult
chemical_list: D007093:Imidazoles; D010091:Oximes; D002244:Carbon; D009584:Nitrogen; C561627:dabrafenib